Intro to lymphomas and myeloma

Question 1

What is lymphoma?

Answer 1

Cancer of white blood cells (lymphocytes)

Affects mature blood cells, mostly B lymphocytes and also T lymphocytes

Heterogenous group

Many known to be due to specific genetic mutations and chromosomal translocations

Question 2

What are the main functions of the lymphatic system?

Answer 2

Blood filtration/purification

Removal of excess fluids from tissue

Absorption and transport of lipids

Immune system activation – produces immune cells

Question 3

What is lymph fluid?

Answer 3

Fluid that accumulates in tiny spaces between tissue cells, contains proteins, fats, lipids and lymphocytes.

Lymph filtered by network of lymph nodes, helps to remove microorganisms and foreign bodies.

Question 4

What are the primary and secondary lymph organs?

Answer 4

Primary lymph organs: sites where stem cells can divide and become immunocompetent. Bone marrow and thymus.

Secondary lymph organs: sites where most of the immune responses occur. These are spleen, lymph nodes, appendix, Peyer’s patches, tonsils and adenoids.

Question 5

How does lymphoma develop?

Answer 5

Chromosomal translocation/ mutation that affects lymphocytes in different maturation stages or mature lymphocytes

Causes uncontrolled division

Consequence: organs where lymphocytes are numerous increase in size.

Causes adenopathy (lymph node increases in size) and splenomegaly (other lymph organs increasing in size)

Lymphocytes can spread to other tissues through lymphatic system, most spread to liver, bone marrow and lungs

Infiltration into bone marrow makes it detectable in the blood and other organs

can also be caused by infections.

Question 6

What are the two main groups lymphomas can be categorised into?

Answer 6

Non-hodgkin’s lymphomas, most common type - 83% of total lymphomas

• incidence increases with age, 6th most common cancer in UK

Hodgkin’s lymphomas - 17% of total lymphomas

• not common, accounts for less than 1% of all new cancer cases

Question 7

What are the symptoms of lymphoma?

Answer 7

Fever

Swelling of the face and neck

Lump in the neck, armpit or groin

Excessive sweating at night

Unexpected weight loss

Itchiness

Breathlessness

Loss of appetite

Feeling of weakness

Question 8

How is lymphoma diagnosed?

Answer 8

Lymph node biopsy, partial or total excision of lymph node to be examinder under microscope - histopathological features

Other tests to identify subtype

• FISH
• Flow cytometry
• NGS
• immunophenotyping

Staging PET, determines which areas of the body are affected

Question 9

What are the different stages of PET?

Answer 9

S1 – only one single node region is affected

S2- involves 2 or more lymph node regions on the same side of diaphragm

S3 – lymph node regions on both sides of the diaphragm

S4- cancer involves 1 or more lymphatic organs

Question 10

What is the aetiology of lymphoma?

Answer 10

Multifactorial disorder

• Malfunctioning of the body’s immune system
• Exposure to certain infections

Triggers are unknown but most of lymphomas occur when a B cell develops/acquires a mutation in its DNA.

What causes the mutation in DNA is unknown

Question 11

What is the presentation of Hodgkin Lymphoma?

Answer 11

Clonal B-cell malignancy

Presentation – non-painful, enlarged lymph node/s

Half of the cases of Hodgkin Lymphoma are due to Epstein Barr virus infection

Other risk factors include family history of lymphoma or having HIV/AIDS

Question 12

What is seen in lymph node biopsy of Hodgkin’s lymphoma?

Answer 12

Hodgkin’s cells - multinucleated red stem cells in lymph nodes

Can observe with light microscope, big.

Derived from B-lymphocytes, bi-lobe nucleus, ‘owl’ eye appearance.

also called Reed-Sternberg cell

Question 13

How is Hodgkin lymphoma treated?

Answer 13

Treatment: Chemotherapy +/- radiotherapy. Stem cell transplant.

Prognosis: 5 year survival, 50-90% depending on age, stage and histology. Especially good results in young adults (97%)

Question 14

What is the presentation of non-hodgkin lymphoma?

Answer 14

Enlarged lymph nodes. Some forms are slow others grow faster.

General lymphoma symptoms – weight loss, fevers, night sweats.

Enlarged lymph nodes may cause lumps that can be felt under the skin.

Question 15

What is the cause of non-hodgkin lymphoma and the risk factors?

Answer 15

Chromosome translocations.

Risk factors:

virus infections e.g EBV (HHV4) in Burkitt’s lymphoma

Human T-cell leukaemia virus in adult t-cell lymphoma

Question 16

Between what chromosomes does translocations occur in?

Answer 16

Ig heavy or light chain in chr14 and another chromosome

Ig genes highly expressed in B-cells

each Ig gene has powerful tissue specific enhancer (high expression levels), enhances expression of these genes

most cases of follicular lymphoma translocation between chr 14 and 18

Question 17

What happens when chromosome translocation occurs?

How does it cause lymphoma?

Answer 17

Enhancer activates promoter or rearranged V segment of the Ig.

Enhances transcription of genes located in other chromosome fused with chr14

for example, chr18 has BCL-2 gene, apoptosis inhibitor.

BCL-2 overexpressed when under regulation of Ig enhancer after translocation

lower rate of apoptosis, inhibits cell proliferation and survival

Question 18

How do we know that virus infections like EBV drive lymphomas in immunosuppressed patients?

Answer 18

It transforms B-lymphocytes in culture due to viral oncogene LMP-1 in immunosuppressed people

cytotoxic T cells can’t attack virus

no longer eliminated by cytotoxic T-cells, develop high grade lymphoma

Question 19

What is a low grade non-hodgkin lymphoma?

Answer 19

Normal tissue architecture partially preserved – normal cell of origin recognisable

Divide slowly

May be present for many months before diagnosis

Behave in an indolent fashion

Question 20

What is a high grade non-hodgkin lymphoma?

Answer 20

Loss of normal tissue architecture – normal cell of origin hard to determine

Divide rapidly

Present for matter of weeks before diagnosis

May be life threatening

Question 21

How is non-hodgkin lymphoma diagnosed?

Answer 21

Immunophenotyping

Cytogenetics – FISH – for chromosome translocations

Light chain restriction - in reactive lymphoid population there is a mixture of kappa and lambda positive cells. Cells expressing kappa light chains outnumber cells expression lambda light chains. Can determine type of NHL

PCR – for clonal Ig gene rearrangement

Question 22

How is NHL treated?

Answer 22

Chemotherapy

Radiotherapy

Stem cell transplant

Monoclonal Ab therapy – Rituximab (anti-CD20, targets CD20 cell surface molecules present in leukaemia and lymphoma B cells). Antibody sticks to all CD20 cell bodies it finds, immune system picks out the marked cells and kills them – Natural killer cells – 80% success rate

Question 23

What is multiple myeloma?

What is its presentation?

What are the risk factors?

Answer 23

Tumour of the bone marrow, involves plasma cells (antibodies production), a type of leukocyte originate in BM and secrete large amounts of AB in response to antigen

Presentation:

absence of initial symptoms, later bone pain, bleeding, frequent infections and anaemia

Cause unknown, risk factors:

obesity, radiation exposure, family history, chemicals

Question 24

What are paraproteins?

Answer 24

Abnormal plasma cells produce abnormal antibodies, paraproteins.

A monoclonal Ig, can be detected in blood or urine.

Characterised by homogenous electrophoretic migration by expression of single chain type - kappa or lambda.

Question 25

What are the three clinical features that paraproteins give rise to?

Answer 25

1. Suppression of normal bone marrow, blood cell and immune cell function. Causes anaemia, recurrent infections and bleeding tendency.
2. Bone resorption and release of calcium

Myeloma cells produce cytokines e.g IL-6, activating release of RANKL cytokine from bm and stromal cells.

Osteoclast activation (lytic lesions of bone, bone pain, fractures). multiple myeloma cells also suppress OPG. Unbalance of normal RANKL and OPG drives osteoclastogenesis, the production of more osteoclasts. Osteoclasts promote bone resorption.

Patients start suffering lytic lesions of bone, bone pain and fractures

Consequence calcium is release from the bone, causing hypercalcaemia – multiple symptoms, including mental disturbance

3. Pathological effects of the paraprotein - (single monoclonal Ig in the serum – high levels – malignancy ).

When paraprotein precipitates in kidney tubules it can cause renal failure

Deposited as amyloid in many tissues

2% of cases develop hyper viscosity syndrome

Increased viscosity of blood leading to

• Stroke
• Heart failure

Question 26

How is multiple myeloma diagnosed?

Answer 26

Serum electrophoresis for paraprotein

Urine electrophoresis

Bone marrow biopsy for increased levels of plasma cells

Erythrocyte sedimentation rate (ESR)- high due to stacking of the RBC, rouleau, because of increase in plasma paraprotein concentration. - ESR can also be high in other conditions like inflammation, non-specific test

flow cytometry and cytogenetics to detect cause

Radiological investigation of skeleton for lytic lesion

Question 27

How is MM treated?

Answer 27

Radiotherapy (recommended when myeloma is localised)

chemotherapy combinations (thalidomide, lenalidomide and bortezomib)

targeted therapies

immunotherapy (CAR-T) and allogeneic hematopoietic stem cell transplantation (ASCT) in young patients

Prognosis: Chemo +ASCT – overall 5-year survival rate 35%